Antiretroviral therapy (ART) does not eradicate HIV and the virus rebounds upon ART interruption. Recently, a sustained control of HIV replication in the absence of ART has been achieved in a subset of subjects starting ART early after infection (post-treatment controllers; PTC). However, the virologic and immunologic determinants of post-ART control of HIV replication are still unclear, particularly in tissues. Understanding the mechanisms behind durably containing HIV replication may guide new strategies towards HIV remission. Here, we used the well-established model of SIV-infected rhesus macaques (RMs) to investigate the features associated with post-ART SIV control.
We identified five SIVmac239-infected RMs (B*08– and B*17–) that, after seven months of ART initiated at two-months p.i., controlled viral rebound (<200 copies/mL) after structured treatment interruption (STI). Blood (PB), rectum (RB) and lymph node samples were longitudinally collected from these animals as well as from RMs that, under the same experimental conditions, experienced a robust SIV rebound after STI (NC). Total SIV-DNA and RNA was measured on purified PB CD4 T cells and mucosal tissues by qPCR; immunological parameters were determined by flow cytometry. Predictors associated with PTC status were evaluated by odds ratio analyses.
Before ART initiation, PTC had markedly reduced SIV-RNA levels in plasma and RB, lower SIV-DNA content in PB CD4 T cells and RB, reduced T-cell activation, and higher CD4 counts as compared to NC (P<0.01 for all measures). Levels of intestinal CD4 T cells were similar, but PTC had higher frequencies of Th17 and Th22 cells. On ART, PTC had significantly lower levels of residual plasma viremia (<3 copies/mL) and SIV-DNA content in PB CD4 T cells. The bulk and SIV-specific CD8 T cell compartment was comparable between the two groups, thus suggesting that PTC can achieve partial viral control without CD8 antiviral responses superior to those of NC. Remarkably, PB and RB SIV-RNA and DNA contents rapidly increased in NC after ART interruption, while remain stable or progressively decreased in PTC. Finally, partial control of SIV rebound in PTC resulted in higher CD4 levels and reduced inflammation in PB, RB and LN during the off-ART period.
Lower pre-ART viremia, cell-associated SIV-DNA, and T cell activation with concomitant preservation of Th17 cell homeostasis are highly associated with prolonged viral control post ART interruption in SIV-infected RMs.